Cycloalkano-indole and -azaindole derivatives

Abstract

Cycloalkano-indole and -azaindole derivatives are prepared by reaction of appropriately substituted carboxylic acids with amines. The cycloalkano-indole and -azaindole derivatives are suitable as active compounds for medicaments, preferably antiatherosclerotic medicaments.

1 . Cycloalkano-indole and -azaindole derivatives of the general formula (I)  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  and R 2 , including the double bond connecting them, together form a phenyl or pyridyl ring or a ring of the formula  
                     wherein    R 8  denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,    
 R 3  and R 4 , including the double bond connecting them, together form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical, 
 or ring systems mentioned under R 1 /R 2  and R 3 /R 4  optionally being substituted up to 3 times by identical or different halogen trifluoromethyl, carboxyl or hydroxyl substituents, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which, for its part, can be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms,  
 
 D represents hydrogen, cycloalkyl having 4 to 12 carbon atoms or straight-chain or branched alkyl having up to 12 carbon atoms,  
 E represents the —CO— or —CS— group,  
 L represents an oxygen or sulphur atom or a group of the formula —NR 9 , 
 wherein  
 R 9  denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or phenyl,  
 
 R 5  represents phenyl or a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the series consisting of S, N and/or O, 
 the cycles optionally being substituted up to 3 times by identical or different nitro, carboxyl, halogen or cyano substituents or by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 6 carbon atoms or by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms,  
 and/or the cycles optionally being substituted by a group of the formula —OR 10  or —NR 11 R 12 ,  
 wherein  
 R 10  denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms,  
 R 11  and R 12  are identical or different and denote phenyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or straight-chain or branched acyl having up to 8 carbon atoms, which is optionally substituted by a group of the formula —NR 13 R 14 , 
 wherein  
 R 13  and R 14  are identical or different and denote hydrogen or straight-chain or branched acyl having up to 8 carbon atoms,  
 
 
 R 6  represents hydrogen, carboxyl or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl or by a group of the formula —O—CO—R 15 , 
 wherein  
 R 15  denotes phenyl which is optionally substituted up to 3 times by identical or different halogen or hydroxyl substituents or by straight-chain or branched alkyl having up to 5 carbon atoms, or straight-chain or branched alkyl or alkenyl each having up to 22 carbon atoms, each of which is optionally substituted by a group of the formula —OR 6 , 
 wherein  
 R 16  is hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl having up to 6 carbon atoms,  
 
 
 R 7  represents hydrogen or  
 R 6  and R 7  together represent the group of the formula ═O,  
 if appropriate in an isomeric form, and their salts.  
 
     
     
         2 . Cycloalkano-indole and -azaindole derivatives of the formula according to  claim 1   
       wherein 
 R 1  and R 2 , including the double bond connecting them, together form a phenyl or pyridyl ring or a ring of the formula  
                     wherein    R 8  denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,    
 R 3  and R 4 , including the double bond connecting them, together form a phenyl ring or a cyclopentene, cyclohexene, cycloheptene, cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene or oxocyclooctene radical, 
 or ring systems mentioned under R 1 /R 2  and R 3 /R 4  optionally being substituted up to 2 times by identical or different fluorine, chlorine, bromine, trifluoromethyl, carboxyl or hydroxyl substituents, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms or by straight-chain or branched alkyl having up to 4 carbon atoms, which, in turn, can be substituted by hydroxyl or by straight-chain or branched alkoxy having up to 3 carbon atoms,  
 
 D represents hydrogen, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or straight-chain or branched alkyl having up to 10 carbon atoms,  
 E represents the —CO— or —CS— group,  
 L represents an oxygen or sulphur atom or represents a group of the formula —NR 9 , 
 wherein  
 R 9  denotes hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxyl or phenyl,  
 
 R 5  represents phenyl, pyridyl, furyl, thienyl or imidazolyl, each of which is optionally substituted up to 2 times by identical or different nitro, carboxyl, fluorine, chlorine, bromine or cyano substituents, by straight-chain or branched alkenyl or alkoxy carbonyl each having up to 4 carbon atoms or by straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 5 carbon atoms, 
 and/or the cycles are optionally substituted by a group of the formula —OR 10  or —NR 11 R 12 ,  
 wherein  
 R 10  denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms,  
 R 11  and R 12  are identical or different and denote phenyl, hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms or denote straight-chain or branched acyl having up to 6 carbon atoms, which is optionally substituted by a group of the formula —NR 13 R 14 , 
 wherein  
 R 13  and R 14  are identical or different and denote hydrogen or straight-chain or branched acyl having up to 6 carbon atoms,  
 
 
 R 6  represents hydrogen, carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally substituted by hydroxyl or by a group of the formula —O—CO—R 5 , 
 wherein  
 R 15  denotes phenyl which is optionally substituted up to 3 times by identical or different fluorine, chlorine, bromine or hydroxyl substituents or by straight-chain or branched alkyl having up to 4 carbon atoms,  
 or straight-chain or branched alkyl or alkenyl each having up to 20 carbon atoms, each of which is optionally substituted by a group of the formula —OR 16 , 
 wherein  
 R 6  is hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl having up to 5 carbon atoms,  
 
 
 R 7  represents hydrogen or  
 R 6  and R 7  together represent the group of the formula ═O,  
 if appropriate in an isomeric form, and their salts.  
 
     
     
         3 . Cycloalkano-indole and -azaindole derivatives of the formula according to  claim 1   
       wherein 
 R 1  and R 2 , including the double bond connecting them, together form a phenyl or pyridyl ring or a ring of the formula  
                     wherein    R 8  denotes hydrogen or methyl,    
 R 3 and R 4 , including the double bond connecting them, together form a phenyl ring or a cyclopentene, cyclohexene, cycloheptene, cyclooctene, oxocyclopentene, oxocyclohexene, oxocycloheptene or oxocyclooctene radical, 
 or ring systems mentioned under R 1 /R 2  and R 3 /R 4  optionally being substituted up to 2 times by identical or different fluorine, chlorine, bromine, trifluoromethyl, carboxyl or hydroxyl substituents, by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 3 carbon atoms or by straight-chain or branched alkyl having up to 3 carbon atoms, which, for its part, can be substituted by hydroxyl, methoxy or ethoxy,  
 
 D represents hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or straight-chain or branched alkyl having up to 6 carbon atoms,  
 E represents the —CO— or —CS— group,  
 L represents an oxygen or sulphur atom or represents a group of the formula —NR 9 , 
 wherein  
 R 9  denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or phenyl,  
 
 R 5  represents phenyl, pyridyl or thienyl, each of which is optionally substituted up to 2 times by identical or different nitro, carboxyl, fluorine, chlorine, bromine or cyano substituents, by straight-chain or branched alkenyl or alkoxycarbonyl each having up to 3 carbon atoms or by straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, carboxyl or by straight-chain or branched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms, 
 and/or the cycles are optionally substituted by a group of the formula —OR 10  or —NR 11 R 12 ,  
 wherein  
 R 10  denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 3 carbon atoms,  
 R 11  and R 12  are identical or different and denote phenyl, hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms or denote straight-chain or branched acyl having up to 5 carbon atoms, which is optionally substituted by a group of the formula —NR 13 R 14 , 
 wherein  
 R 13  and R 14  are identical or different and denote hydrogen or straight-chain or branched acyl having up to 5 carbon atoms,  
 
 
 R 6  represents hydrogen, carboxyl or straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl or by a group of the formula —O—CO—R 15 , 
 wherein  
 R 15  denotes phenyl which is optionally substituted up to 3 times by identical or different straight-chain or branched alkyl having up to 3 carbon atoms, 
 or denotes straight-chain or branched alkyl or alkenyl each having up to 19 carbon atoms, each of which is optionally substituted by a group of the formula —OR 16 ,  
 wherein  
 R 16  denotes hydrogen, benzyl, triphenylmethyl or straight-chain or branched acyl having up to 4 carbon atoms,  
 
 
 R 7  represents hydrogen or  
 R 6  and R 7  together represent the group of the formula ═O,  
 if appropriate in an isomeric form, and their salts.  
 
     
     
         4 . Cycloalkano-indole and -azaindole derivatives according to  claim 1  wherein such compound is 2-[4-(2,4-dimethyl-5,6,7,8-tetrahydro-α-carboline-9-yl) methyl-phenyl]-2-cyclopenthyl-acetic acid N-[(R)-phenylglycinolamide] of a formula  
       
         
           
           
               
               
           
         
       
       in form of their isomeres their recamic mixtures and salts thereof.  
     
     
         5 . Cycloalkano-indole and -azaindole derivatives according to  claim 1  wherein such compound is 2-[4-(2,4-dimethyl-α-carboline-9-yl)methyl-phenyl]-2-cyclopenthyl-acetic acid N-[(R)-phenylglucynolamide] of the formula  
       
         
           
           
               
               
           
         
       
       in form of their enanciomeres their racemates and salts thereof.  
     
     
         6 . Cycloalkano-indole and -azaindole derivatives according to  claim 1  wherein such compound is 1-(R,S)-1-Phenyl)-2-triphenylmethyloxy-ethyl[2-(R,S)-2-[4-(2,4-dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetate of the formula  
       
         
           
           
               
               
           
         
       
       in form of their isomeres, their racemates and salts thereof.  
     
     
         7 . Cycloalkano-indoles and -azaindoles according to  claim 1  wherein such compound is 2-(R,S)-2-[4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl]-2-cyclopentyl-acetic acid [N-(1-(R,S)-1-phenyl-1 carboxy-methyl]-amide of the formula  
       
         
           
           
               
               
           
         
       
       in form of their isomeres, their racemates and salts thereof.  
     
     
         8 . A composition for the treatment of ateroscleroses comprising an amount effective therefor of a compound or salt thereof according to  claim 1  and a pharmacologically ecaptable diluent.  
     
     
         9 . The method of treating ateroscleroses in a pationt in need thereof which comprises atministering to such patient an amount effective therefor of a compound or salt thereof according to claim  1 .